The protein kinase C family is a group of serine/threonine kinases that is comprised of twelve related isoenzymes. These kinases are expressed in a wide range of tissues and cell types. Its members are encoded by different genes and are sub-classified according to their requirements for activation. The classical PKC enzymes (cPKC) require diacylglycerol (DAG), phosphatidylserine (PS) and calcium for activation. The novel PKC's (nPKC) require DAG and PS but are calcium independent. The atypical PKC's (aPKC) do not require calcium or DAG.
PKC-theta is a member of the nPKC sub-family. It has a restricted expression pattern, found predominantly in T cells and skeletal muscle. Upon T cell activation, a supramolecular activation complex (SMAC) forms at the site of contact between the T cell and antigen presenting cell (APC). PKC-theta is the only PKC isoform found to localize at the SMAC (C. Monks et al., Nature, 1997, 385, 83), placing it in proximity with other signaling enzymes that mediate T cell activation processes. In another study (G. Baier-Bitterlich et al., Mol. Cell. Biol., 1996, 16, 842) the role of PKC-theta in the activation of AP-1, a transcription factor important in the activation of the IL-2 gene, was confirmed. In unstimulated T cells, constitutively active PKC-theta stimulated AP-1 activity while in cells with dominant negative PKC-theta, AP-1 activity was not induced upon activation by PMA. Other studies showed that PKC-theta, via activation of IκB kinase beta, mediates activation of NF-κB induced by T cell receptor/CD28 co-stimulation (N. Coudronniere et al., Proc. Nat. Acad. Sci. U.S.A., 2000, 97, 3394; X. Lin et al., Moll. Cell. Biol., 2000, 20, 2933). Proliferation of peripheral T cells from PKC-theta knockout mice, in response to T cell receptor (TCR)/CD28 stimulation was greatly diminished compared to T cells from wild type mice. In addition, the amount of IL-2 released from the T cells was also greatly reduced (Z. Sun et al., Nature, 2000, 404, 402). Otherwise, the PKC-theta knockout mice seemed normal and were fertile.
The studies cited above and other studies confirm the critical role of PKC-theta in T cell activation and subsequent release of cytokines such as IL-2 and T cell proliferation (A. Altman et al., Immunology Today, 2000, 21, 567). Thus an inhibitor of PKC-theta would be of therapeutic benefit in treating immunological disorders and other diseases mediated by the inappropriate activation of T cells.
It has been well established that T cells play an important role in regulating the immune response (Powrie and Coffman, Immunology Today, 1993, 14, 270). Indeed, activation of T cells is often the initiating event in immunological disorders. Following activation of the TCR, there is an influx of calcium that is required for T cell activation. Upon activation, T cells produce cytokines, including IL-2, leading to T cell proliferation, differentiation, and effector function. Clinical studies with inhibitors of IL-2 have shown that interference with T cell activation and proliferation effectively suppresses immune response in vivo (Waldmann, Immunology Today, 1993, 14, 264).
Accordingly, agents that inhibit T lymphocyte activation and subsequent cytokine production are therapeutically useful for selectively suppressing the immune response in a patient in need of such immunosuppression and therefore are useful in treating immunological disorders such as autoimmune and inflammatory diseases.
In addition, PKC theta activation has been shown to be associated with insulin resistance in skeletal muscle (M. E. Griffen et al., Diabetes, 1999, 48, 1270). Therefore inhibitors of PKC-theta may also be useful for treating type II diabetes.
Dahmann et al, U.S. application Ser. No. 10/271,763, filed Oct. 16, 2002, (now U.S. Patent Application Publication No. 2003/0171359 A1) discloses pyrimidine derivatives as inhibitors of various protein kinases such as SRC kinase, PLK kinase and particularly cyclin-dependent kinases (CDKs) and Aurora B. WO 00/75113 and U.S. Pat. No. 6,432,963 describe pyrimidine carboxamides as inhibitors of Syk tyrosine kinase. WO 01/00213 discloses heteroaryl substituted pyrimidines as SRC kinase inhibitors. WO 97/19065 describes substituted 2-anilinopyrimidine compounds as inhibitors of certain protein kinases. WO 02/096887 and WO 02/096888 both disclose 2-anilinopyrimidine derivatives as inhibitors of cyclin-dependent kinases. WO 03/106451 discloses certain substituted diaminopyrimidine compounds as inhibitors of PKC-theta.
There is a continuing need in the art for compounds that are potent and selective inhibitors of PKC-theta.